- Rational drug design to explore the structure-activity relationship (SAR) of TRK inhibitors with 2,4-diaminopyrimidine scaffold
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Tropomyosin receptor kinase (TRK) is an ideal target for treating cancers caused by the NTRK gene fusion. In this study, more than 60 2,4-diaminopyrimidine derivatives were prepared to understand the structure-activity relationship and confirm the rationality of the pharmacophore model reported previously. Among them, compound 19k was found to be a potent pan-TRK inhibitor that inhibits the proliferation of Km-12 cell lines. Additionally, compound 19k induced the apoptosis of Km-12 cells in a concentration-dependent manner. Western blot analysis revealed that compound 19k inhibited the phosphorylation of TRK to block downstream pathways. Compound 19k also possessed outstanding plasma stability and liver microsomal stability in vitro, with half-lives greater than 289.1 min and 145 min, respectively. Pharmacokinetic studies indicated that the oral bioavailability of compound 19k is 17.4%. These results demonstrate that compound 19k could serve as a novel lead compound for overcoming NTRK-fusion cancers.
- Wu, Tianxiao,Qin, Qiaohua,Liu, Nian,Zhang, Chu,Lv, Ruicheng,Yin, Wenbo,Sun, Yin,Sun, Yixiang,Wang, Ruifeng,Zhao, Dongmei,Cheng, Maosheng
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- Design, synthesis and biological evaluation of N-hydroxy-aminobenzyloxyarylamide analogues as novel selective κ opioid receptor antagonists
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Aminobenzyloxyarylamide derivatives 1a-i and 2a-t were designed and synthesized as novel selective κ opioid receptor (KOR) antagonists. The benzoyl amide moiety of LY2456302 was changed into N-hydroxybenzamide and benzisoxazole-3(2H)-one to investigate whether it could increase the binding affinity or selectivity for KOR. All target compounds were evaluated in radioligand binding assays for opioid receptor binding affinity. These efforts led to the identification of compound 1c (κ Ki = 179.9 nM), which exhibited high affinity for KOR. Moreover, the selectivity of KOR over MOR and DOR increased nearly 2-fold and 7-fold, respectively, compared with (±)LY2456302.
- He, Guangchao,Peng, Kewen,Song, Qiao,Wang, Junwei,Xu, Anhua,Xu, Yungen,Zhu, Qihua
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- Stereocomplementary Synthesis of Pharmaceutically Relevant Chiral 2-Aryl-Substituted Pyrrolidines Using Imine Reductases
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Exploring a collection of naturally occurring imine reductases (IREDs) identified two stereocomplementary IREDs with reducing activity toward sterically hindered 2-aryl-substituted pyrrolines. Using (R)-selective ScIR and (S)-selective SvIR, various chiral 2-aryl-substituted pyrrolidines with excellent enantioselectivity (>99% ee) were stereocomplementarily synthesized in good yield (60-80%), demonstrating the feasibility of IREDs for generating pharmaceutically relevant chiral 2-aryl-substituted pyrrolidine intermediates.
- Chen, Fei-Fei,Chen, Qi,Li, Bo-Bo,Xu, Jian-He,Zhang, Yu-Hui,Zheng, Gao-Wei,Zhou, Xin-Yi
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supporting information
p. 3367 - 3372
(2020/04/21)
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- Enantioselective Synthesis of 2-Substituted Pyrrolidines via Intramolecular Reductive Amination
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Catalyzed by the complex generated in situ from iridium and the chiral ferrocene ligand, tert -butyl (4-oxo-4-arylbutyl)carbamate substrates were deprotected and then reductively cyclised to form 2-substituted arylpyrrolidines in a one-pot manner, in which the intramolecular reductive amination was the key step. A range of chiral 2-substituted arylpyrrolidines were synthesised in up to 98percent yield and 92percent ee.
- Chang, Mingxin,Guo, Haodong,Huang, Haizhou,Zhang, Tao,Zhao, Wenlei,Zhou, Huan
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p. 2713 - 2719
(2019/06/19)
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- Preparation method of (R)-2-(2-substitution-5-fluorobenzene)pyrrolidine
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The invention belongs to the technical field of organic synthesis, and provides a preparation method of (R)-2-(2-substitution-5-fluorobenzene)pyrrolidine. The preparation method comprises the following steps of: taking 2-substitution-5-fluorobenzaldehyde
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- Enantioselective Direct Synthesis of Free Cyclic Amines via Intramolecular Reductive Amination
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Chiral cyclic amines can be prepared via intramolecular reductive amination of N-Boc-protected amino ketones in a one-pot process. With the complex of iridium and f-spiroPhos as the catalyst, a range of N-Boc-protected amino ketones are smoothly transformed into chiral cyclic free amines in high yields and excellent enantioselectivities (up to 97% ee). Moreover, this method can also be successfully applied to the synthesis of a κ-opioid receptor selective antagonist, (S)-1.
- Zhang, Ying,Yan, Qiaozhi,Zi, Guofu,Hou, Guohua
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supporting information
p. 4215 - 4218
(2017/08/23)
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- Design, synthesis and biological evaluation of aminobenzyloxyarylamide derivatives as selective κ opioid receptor antagonists
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Opioid receptors play an important role in both behavioral and mood functions. Based on the structural modification of LY2456302, a series of aminobenzyloxyarylamide derivatives were designed and synthesized as κ opioid receptor antagonists. The κ opioid receptor binding ability of these compounds were evaluated with opioid receptors binding assays. Compounds 1a-d showed high affinity for κ opioid receptor. Especially for compound 1c, exhibited a significant Kivalue of 15.7?nM for κ opioid receptor binding and a higher selectivity over μ and δ opioid receptors compared to (±)LY2456302. In addition, compound 1c also showed potent κ antagonist activity with κ IC50?=?9.32?nM in [35S]GTP-γ-S functional assay. The potential use of the representative compounds as antidepressants was also investigated. The most potent compound 1c not only exhibited potent antidepressant activity in the mice forced swimming test, but also displayed the effect of anti-anxiety in the elevated plus-maze test.
- Wang, Junwei,Song, Qiao,Xu, Anhua,Bao, Yu,Xu, Yungen,Zhu, Qihua
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- Synthesis of chiral cyclic amines via Ir-catalyzed enantioselective hydrogenation of cyclic imines
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A highly enantioselective hydrogenation of cyclic imines for synthesis of chiral cyclic amines has been realized. With the complex of iridium and (R,R)-f-spiroPhos as the catalyst, a range of cyclic 2-aryl imines were smoothly hydrogenated under mild conditions without any additive to provide the corresponding chiral cyclic amines with excellent enantioselectivities of up to 98% ee. Moreover, this method could be successfully applied to the synthesis of (+)-(6S,10bR)-McN-4612-Z.
- Zhang, Ying,Kong, Duanyang,Wang, Rui,Hou, Guohua
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p. 3006 - 3012
(2017/04/11)
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- A Kinome-Wide Selective Radiolabeled TrkB/C Inhibitor for in Vitro and in Vivo Neuroimaging: Synthesis, Preclinical Evaluation, and First-in-Human
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The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [11C]-(R)-3 ([11C]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on extensive human kinome vetting, we show that (R)-3 is the most potent and most selective TrkB/C inhibitor characterized to date. It is demonstrated that [11C]-(R)-3 readily crosses the blood-brain barrier (BBB) in rodents and selectively binds to TrkB/C receptors in vivo, as evidenced by entrectinib blocking studies. Substantial TrkB/C-specific binding in human brain tissue is observed in vitro, with specific reduction in the hippocampus of Alzheimer's disease (AD) versus healthy brains. We additionally provide preliminary translational data regarding the brain disposition of [11C]-(R)-3 in primates including first-in-human assessment. These results illustrate for the first time the use of a kinome-wide selective radioactive chemical probe for endogenous kinase PET neuroimaging in human.
- Bernard-Gauthier, Vadim,Bailey, Justin J.,Mossine, Andrew V.,Lindner, Simon,Vomacka, Lena,Aliaga, Arturo,Shao, Xia,Quesada, Carole A.,Sherman, Phillip,Mahringer, Anne,Kostikov, Alexey,Grand'Maison, Marilyn,Rosa-Neto, Pedro,Soucy, Jean-Paul,Thiel, Alexander,Kaplan, David R.,Fricker, Gert,W?ngler, Bj?rn,Bartenstein, Peter,Schirrmacher, Ralf,Scott, Peter J. H.
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p. 6897 - 6910
(2017/09/07)
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- COMPOUNDS AND COMPOSITIONS AS TRK INHIBITORS
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The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated TRK kinase activity.
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- COMPOUNDS AND COMPOSITIONS AS TRK INHIBITORS
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The invention provides compounds of formula (I), pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated TRK kinase activity. wherein: and the rest of the variables are as specified in the claims.
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- SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS
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Compounds of Formula (I) and salts thereof in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
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Page/Page column 72
(2011/02/24)
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- SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS
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Compounds of Formula (I) in which R1, R2, R3, R4, X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor.
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Page/Page column 51
(2010/05/13)
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- COMPOUNDS AND COMPOSITIONS AS KINASE INHIBITORS
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The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly Ros, KDR, FMS, c-FMS, FLT3, c-Kit, JAK2, JAK3, Aurora, PDGFR, Lck, TrkA, TrkB, TrkC, IGF-1R, ALK4, ALK5 and ALK or combinations thereof.
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- 1-arenesulfonyl-2-aryl-pyrrolidine and pyridine derivatives
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1-Arenesulfonyl-2-Aryl-pyrrolidine and pyridine derivatives having activity as ligands of metabotropic glutamate receptors of the formula are disclosed.
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